1. rFactor VIIa in Cardiac Surgery
Timothy H. Trotter, MD, FACS
Assistant Professor of Surgery

2. IRB Approval
OUHSC IRB Protocol #12376
VAMC IRB Protocol #12376

3. Assistance Mary Lane, PhD -- Data analysis
Shannie Frisbie -- Cost information
The residents and fellows for providing me with the opportunity to use rFVIIa

4. FDA Approved Uses for rFactor VIIa
“…management of bleeding related to hemophilia in patients with factor inhibitors…”
A number of “off label” uses have become popular since it was first used for treatment of traumatic bleeding after a GSW in 1999

5. Clotting Factor Changes in CPB
Davidson, et al. Blood Coagulation & Fibrinolysis 2003; 14:
Clotting Factor Changes in CPB
Decrease in Factors may be important in CPB
Harker -- decrease in Factors not important
Based on observations of single deficiency pts
The following changes have been observed :
Factor II 51% Decrease
Factor V 28% Decrease
Falls before CPB
Less fall with adequate heparinization
Factor VII 27% Decrease
Ca. 28% fall in the PCV due to dilution
Factor X 56% Decrease
Factor VIII No Change

6. rFactor VIIa Mechanism of Action
406 amino acid Vitamin K-dependent glycoprotein
Generation of thrombin by initial binding to tissue factor and activation of FX on the platelet surface
It also participates in conversion FIX-->FIXa
Activation of FX in combination with FV converts prothrombin to thrombin leading to the formation of a hemostatic “plug” & subsequently converts fibrinogen to fibrin causing local hemostasis

7. rFactor VIIa Mechanism of Action
Partial activation of thrombin occurs at rFVIIa concentrations of 50nM, but full activation of thrombin or “thrombin burst” occurs at nM
This thrombin activity on the platelet leads to a stabilized thrombin plug and tight fibrin structure resistant to lysis

8. rFactor VIIa Mechanism of Action
The “thrombin burst” and stabilized “plug” seems to only occur at sites where tissue factor is exposed at sites of vessel injury
This is probably why there is little generalized thrombosis with rFVIIa

9. rFactor VIIa Mechanism of Action
The decrease in fibrinolysis is thought to possibly be due to an increase in thrombin-activatable fibrinolysis inhibitor and an increase in FXIIIa
rFVIIa appears to work in a TF-independent fashion directly on FIX/FX on the phospholipid surface of the activated platelet

10. Hemostatic Mechanisms for rFVIIa
Eikelboom, et al. Blood Coagulation & Fibrinolysis 2003, 14:
Hemostatic Mechanisms for rFVIIa

11. rFactor VIIa Half Life
The mean elimination half life of rFVIIa is hours (only 1.3 hours in children)
Prothrombin time is shortened by rFVIIa treatment

12. rFactor VIIa Dosing Dosage Micrograms/Kg Time to Treatment
Excellent or Effective Response %
Mean Number of Doses
Compassionate Use
60-120
5 days 72
13.6
Dose Finding 70
9 hours
3.6 35 53
3.5
US Home Treatment 90
1.2 hours 92
2.3

13. rFactor VIIa Dosing
Most authors will admit that there is little real science for the dosing of rFVIIa and most authorities recommend that the dosing be based on weight, but that the dose be rounded to the nearest vial
Continuous infusions do not seem to provide any benefit and the dosing scheme is no more clear than bolus

14. Adverse Effects of rFVIIa
Novo Nordisk data, rFVIIa, 20 March 2001.
Adverse Effects of rFVIIa
As of March 2001, an estimated 171,790 doses had been sold with 87 reported adverse events:
16 Decreased therapuetic response
7 MI’s (all pt’s had predisposing factors)
4 PE’s
6 Ischemic CVA’s
3 Venous Thromboses
1 DIC
17 died and 8 were felt to be related to the rFVIIa
1:21,474 related to rFVIIa

15. Adverse Effects of rFVIIa
Levi, et al. Crit Care Med 2005; 33:
Adverse Effects of rFVIIa
Levi et al reviewed 483 papers related to the pharmacologic use of rFVIIa
Used for hemophilia with inhibiting antibodies, Glanzmann Thrombasthenia, congenital FVII deficiency, liver disease, cirrhosis, surgery/trauma, reversal of anticoagulant therapy, and excessive blood loss
They found that in patients other than hemophilia patients the estimated incidence of thromboembolism is 1.4%

16. Surgical Uses of rFVIIa
Raobaikady, et al. BJA 94(5):
Surgical Uses of rFVIIa
Raobaikady et al looked at the use of rFVIIa in a double-blind, randomized, placebo-controlled study in 48 patients undergoing surgery for major traumatic fracture of the pelvis or the pelvis/acetabulum and found no decrease in the volume of blood loss in patients with normal hemostasis

17. Cardiac Surgery and rFVIIa
Karkouti, et al. Transfusion 2005; 45:26-34.
Cardiac Surgery and rFVIIa
Karkouti et al looked at 51 patients with intractable blood loss after cardiac surgery using a propensity score-matched case-control analysis
They used about 70micrograms/kg in severe bleeding and 35micrograms/kg in “less severe, controlled bleeding”

18. Characteristics of Karkouti Pts
Karkouti, et al. Transfusion 2005; 45:26-34.
Characteristics of Karkouti Pts
VARIABLE
rFVIIa PATIENTS %
GENERAL POP %
p VALUE
Mean Age 56 62
0.0007
Urgent Surgery 27 8
<0.0001
Redo Surgery 35
CHF 48 21
Active Endocarditis 1
Complex Surgery 73 24
Mean CPB Period (min)
159
100
DHCA 15 3
Difficult Wean from CPB 46 13
LCOS 25 4
Reexploration 60 6
Massive Blood Loss 92
Units Blood, Cryoppt 10
PRBC 14
Platelets
FFP

19. Karkouti, et al. Transfusion 2005; 45:26-34.
Matched Control Pts
The matched control patients were essentially no different from the rFVIIa patients except in the volume of blood products that they received

20. Postoperative Course Karkouti Pts
Karkouti, et al. Transfusion 2005; 45:26-34.
Postoperative Course Karkouti Pts
ADVERSE EVENT
GENERAL POP
rFVIIa PATIENTS
MATCHED CONT PT
Recovery Measures
Duration Intub (hrs) 14 62 64
ICU LOS (days) 1 6
3.5 (p <0.05)
Hosp LOS (days) 7
15.5
10 (p <0.05)
Adverse Event
CVA
1.4 4 MI
2.2 3
PE/DVT
0.2
Liver Dysfunction
N/A 2
Renal Dysfunction 15
6 (p <0.05)
Death
0.4
Composite 21

21. Karkouti, et al. Transfusion 2005; 45:26-34.
Karkouti Conclusions
The hourly blood loss profile after the administration of rFVIIa is similar to that seen in the control and is significant
1/3 of the patients required a second dose and all of those patients had a surgically correctable cause
rFVIIa was found to reduce intractable blood loss, but with an increase in morbidity
ICU LOS, Hosp LOS, Renal Dysfunction, ? CVA

22. Cardiac Surgery and rFVIIa
Ravio et al, Ann Thorac Surg 2005; 80:66-71.
Cardiac Surgery and rFVIIa
Raivio et al reported the use of rFVIIa in 16 postop cardiac surgery patients
10 patients were “emergency”
6 patients required DHCA
4 were redo patients
All were complex cardiac or aortic procedures
Mean predicted EuroSCORE mortality was 19.8%
Hospital mortality was 25%
Mean ICU stay was 21 days
Mean dose was 65 micrograms/kg

23. Raivio Bleeding Pre/Post rFVIIa
Ravio et al, Ann Thorac Surg 2005; 80:66-71.
Raivio Bleeding Pre/Post rFVIIa
6 Hours Before rFVIIa
6 Hours After rFVIIa
p Value
Bleeding (ml)
2180
350
<0.001
Transfusions (Units)
Platelets 12
0.005
FFP
3.0
1.0
0.017
PRBC
4.0
2.0 NS

24. Ravio et al, Ann Thorac Surg 2005; 80:66-71.
Raivio Conclusions
82% of the patients had an obvious hemostatic response
25% had “severe postoperative thromboembolic or thrombotic complications”
All of the Heart or Heart/Lung transplant patients died
They recommend caution in the use of rFVIIa

25. Cost Concerns The cost of rFVIIa is significant
1.2 mg, 2.4mg, and 4.8 mg vials
2.4 mg “costs” $850 at VAMC
2.4 mg “costs” $2184 at OUMC
Estimated cost in literature is about $5000 for a 90 mcg/kg dose in a 70kg patient
Cost to OUMC 8/04-8/05 for 46 doses in 35 patients was $299,240
However, the cost of intractable bleeding is also high
Average incremental increase in cost of $3,866
Bleeding requiring reexploration increases mortality 7-fold (15.4%) and the additional cost is $10,000

26. Oklahoma City VAMC and rFVIIa
rFVIIa was first used at the OKC VAMC for intractable post-Cardiotomy bleeding in December 2002
Since that time 16/564 patients have received rFVIIa

27. Demographics 16 patients Mean Age 63.9 yrs (54-76) Elective 37.5%
Urgent %
Emergency %
Amicar %
Aprotinin 75%
Nothing %
Few of these patients were receiving IIb/IIIa inhibitors/Plavix

28. Patient Characteristics
Mean Preop EF 49%
Mean rFVII Dose mcg/kg
Mean NYHA/CCS /2.94
Mean CPB Time min
One OPCAB Patient
Mean Operative Time 413 min
Mean Intubation Time 53 hours
Mean SICU Days days
Mean Hospitalization Days days

31. Total Blood Product Use

32. Blood Usage in Pts With rFVIIa Postop

33. Cell Saver Use Pre/Post-FVII

34. PRBC Use Pre/Post-FVII

35. Platelet Use Pre/Post-FVII

36. FFP Use Pre/Post-FVII

37. Cryoppt Use Pre/Post-FVII

38. Chest Tube Output/Hr

39. Outcomes 2/16 patients were returned to the OR for re-exploration
One was bleeding from a side branch of a SVG
One had stopped bleeding and had only about ml of blood total in the left chest and mediastinum
This represents all of the patients returned (with or without rFVIIa) for the past 4 years

40. Mortality 6/16 patients died
1/16 (6.25%) died in the OR/within 30 days
5/16 died from 36 to 208 days later
31.25% overall mortality for these patients
Overall mortality 4.1% (23/564) from 12/02-7/05
5/16 of these deaths were attributed as Operative Mortality by CICSP and these are included in the 4.1%

41. Time To Death

42. Future Directions
rFVIIa, while expensive, may be less expensive than re-exploration
rFVIIa may salvage some patients who otherwise would not have survived
Is there a role for rFVIIa earlier in the care of these patients?

43. Other Issues Other Off-label uses for rFVIIa
Relative contraindications to transfusion
Multiple RBC allo-antibodies
Refractoriness to platelet transfusions
?? Plavix poisoning
IgA deficiency who should not get FFP
Jehovah’s Witnesses
When is the best time to give rFVIIa?
Who decides who gets and when to give rFVIIa?